The prevalence of overweight in children and adolescents has tripled during the past 30 years, and more than 60% of US adults are now overweight. The alarming rise in body weight in both children and adults has likely occurred because the current environment affords easy access to calorie-dense foods and requires less voluntary energy expenditure. However, this environment leads to obesity only in those individuals whose body weight regulatory systems are not able to control body adiposity with sufficient precision in our high calorielow activity environment, which suggests there are subgroups in the US with a uniquely high susceptibility to weight gain under the prevailing environmental conditions. Indeed, certain ethnic and racial subgroups, such as Black and Hispanic Americans, do appear to have more difficulty matching energy intake and energy output in this environment, predisposing them to a greater incidence of overweight and obesity. During adolescence, African American and Hispanic boys and girls experience a steady rise in BMI such that twice as many African American and Hiispanic girls and boys have a BMI above the 95th percentile. These differences in prevalence are not fully accounted for by socioeconomic or cultural factors. The greater adiposity of African American and Hispanic children and adolescents confers risks for obesitys co-morbid conditions, such as Type 2 diabetes, hypertension, and atherosclerotic cardiovascular disease. These obesity-related comorbid conditions contribute to the greater mortality found in some minority groups in the US. However, data also suggest that the predictive risk factors related to body composition and the therapeutic approaches for these comorbid conditions that are derived from the study of Caucasians may be less applicable to those of differing ethnicity or race. Effective prevention and treatment of these obesity-related disorders requires a better understanding of the key elements for body weight regulation. The research of the Unit on Growth and Obesity is directed at increasing our understanding of the genetic and environmental factors involved in determining body weight regulation and body composition during childhood, with a special emphasis on minority populations. Using classical association studies, we have been studying polymorphisms in genes involved in the leptin signaling pathway, to attempt to identify gene variants impacting on body composition that have differing frequency in African American and Caucasian children. Genes currently under study include proopiomelanocortin, the melanocortin receptors 3, 4, and 5, neuropeptide Y and its receptors, brain derived neurotrophic factor (BDNF), and the BDNF receptor TrkB. We have found that polymorphisms in the melanocortin 3 receptor that affect its function by decreasing protein expression are associated with overweight in both African American and Caucasian children, and appear to be more prevalent in African American children. These findings suggest melanocortin 3 receptor variation may be one of the factors predisposing African Americans to high body adiposity. In addition, we have studied genes important for energy expenditure, such as the mitochondrial uncoupling proteins, and studied other genes in the leptin signaling pathway. We have found that alterations in the POMC sequence are more prevalent in African American children, but are not associated with excess body weight in African American and Caucasian children. Recently, we have also studied BDNF serum concentrations in individuals with genetic mutations expected to alter BDNF and TrkB gene function, finding that low serum BDNF is identified with a subset of individuals with obesity. We have subsequently been studying children with the WAGR syndrome, who have deletions of the short arm of chromosome 11, where BDNF is found. Because in Caucasians, amount of visceral fat is highly associated with the complications of obesity, we have studied the distribution of adipose tissue in African American and Caucasian children. We have found that there is less visceral abdominal adipose tissue in non-obese and obese African American children than Caucasian children, but considerably greater insulin resistance in African American children, assessed through hyperglycemic and euglycemic clamp studies. These results imply the relationship between visceral fat and the complications of obesity are different in African Americans and Caucasians. The susceptibility to weight gain in African American may also result from differences in metabolic efficiency: we have also found that resting energy expenditure is approximately 90 kcald less in African American than in Caucasian normal weight and overweight boys and girls. Our studies suggest that these differences are not explained by difference in the hormone leptin but may be due to differences in appendicular skeletal mass. In ongoing protocols, we are studying normal weight African American and Caucasian children and adolescents, African American and Caucasian children who are already obese, and the non-obese African American and Caucasian children of obese parents, in order to study how racial differences in body composition, metabolic rate, insulin sensitivity, glucose disposal, or genetic factors believed to regulate adiposity, such as the uncoupling proteins, leptin and its downstream effectors, and genes that affect energy expenditures such as the beta-3 adrenergic receptor, affect the growth of adipose tissue. Psychological and behavioral factors, such as propensity to engage in binge eating behavior, are also examined. We have found that 6-11 year old children endorsing binge eating behaviors have greater adiposity and a greater propensity for weight gain than those who never report binge eating behaviors. Children are being studied longitudinally into adulthood. We hypothesize that differences in these factors will predict the development of obesity in the populations studied, and may be of great importance in developing rational approaches for the prevention and treatment of obesity in the diverse US population. Given the rapid increase in the prevalence of obesity, the development of treatments for obesity in childhood is urgently needed. In ongoing clinical protocols, we are studying approaches to the control of body weight in children. We have completed a pilot study demonstrating that severely overweight African American and Caucasian adolescents can lose weight when enrolled in a comprehensive weight management program that includes the gastrointestinal lipase inhibitor, orlistat as an adjunct to a behavioral modification program. We have also found evidence that one mechanism through which orlistat may affect body weight is by changing the hedonic value of dietary fat. A randomized controlled trial (RCT) using orlistat is currently underway in 200 severely overweight African American and Caucasian adolescents who have one or more comorbid condition associated with obesity. A second RCT examines the mechanism by which another novel weight loss agent, metformin, may affect the body weight of younger children who have hyperinsulinemia. Because younger children undergo substantial linear growth, agents that promote weight stability such as metformin may be of greater benefit in improving body mass index for children aged 6-12y. A third RCT examines the role of supplemental dietary calcium for body weight regulation. Pilot investigations to study the effects of interpersonal therapy, and to evaluate the impact of increasing non-exercise activity thermogenesis in overweight children are also underway.